Cognitive and memory impairments associated with normal aging and neurodegenerative disease are emerging as one of our nation's greatest health concerns. Therapeutic exercise has emerged as a non- invasive technique to improve learning, memory and cognition in both healthy and neurologically compromised populations. We posit a novel position that exercise-induced improvements in learning and memory are driven by two factors: First, acute rises in brain derived neurotrophic factor (BDNF) enhance memory; and second, the protracted increases in neurotrophins lead to a selective rescue of basal forebrain cholinergic neurons that co-express nestin that ultimately produces an increase in synaptic efficacy. These enhancements intensify activity-related acetylcholine (ACh) release within the septohippocampal circuit and this is what produces the delayed improvements in learning after exercise. This work will advance the field by providing proof of principle for a new mechanistic theory for how exercise can lead to improved cognitive functioning based on the modulation of the cholinergic system. In this proposal we will determine whether sustained exercise-induced release of neurotrophins, in particular nerve growth factor (NGF), will rescue a select population of cholinergic forebrain neurons that co-express nestin from a hypotrophic quiescent state produced by thiamine deficiency in a rodent model of amnesia (AIM 1). In addition, we will demonstrate the exercise-facilitated improvements in activity-dependent release of BDNF and ACh are time-dependent and uniquely drive the enhancement of different cognitive processes. Moreover, exercise activation of TrkA or TrkB receptors selectively upregulate critical synaptic proteins involved in the distinct temporal profile of neurochemical release and behavioral improvement (AIM 2). Developing both behavioral and pharmacological therapeutic interventions for cognitive/memory disorders requires a greater understanding of how the pathological brain reacts and adapts differently from the healthy brain. Such critical pre-clinical information is needed to improve the development of therapeutic strategies that are effective for the recovery of cognitive functions.